Ralph Isberg, Editorial Advisor and former Section Editor for PLOS Pathogens, remembers his friend, colleague, and mentor Stanley Falkow, and reflects on his contributions to the understanding of bacterial pathogens and his commitment to mentorship.
When I first entered the Falkow lab as a postdoctoral fellow in December 1983, I possessed a strange combination of naivete and arrogance that played to Stanley’s strengths. This allowed him to shut down the still and extremely small voice in his head that said: “Maybe this is a bad idea.” Only after success occurred, and I imagine only very rarely, did he ever reveal evidence of this voice.
My background was as a bacterial geneticist: I knew that with a strong enough genetic selection, all the problems of the world could be solved. Stanley’s attitude was that in his lab, you could do anything. He felt that what held other people back was self-doubt and their persistent belief that things were more difficult than they truly were. It is easy to see how these two personalities amplified each other. His attitude was based on twenty years of mentoring experience, whereas mine was borne from ignorance. This is not to say that Stanley took advantage of ignorant postdocs; rather, his perfect disciple was the worker whose mind was not cluttered with negative thoughts about what could go wrong. This is why he was such an incredible mentor to graduate students who had the hubris of inexperience.
Shortly after arriving in the lab, the two of us decided that I should determine how enteropathogenic Yersinia could enter into normally nonphagocytic cultured cells, a property that Dan Portnoy had discovered during his graduate school work in Stanley’s lab. As Stanley put it, “Why don’t you clone invasion?” I took him totally literally, which was to put DNA from Yersinia into E. coli and perform a genetic selection (of course) using mammalian cells as the selective agent, to isolate E. coli strains that could enter cells. This worked surprisingly rapidly, and the evidence was sitting in front of him, on fixed coverslips having Giemsa-stained HeLa cells with E. coli K12 inside of them. “This is brilliant,” he said, “who would have thought that you could use a cell line to select for cloned genes in E. coli?” Now I was really confused, because I certainly thought that this was what he wanted me to do. I basically felt like I was just following directions. “Oh, I said to clone invasion because I knew you would figure out how Yersinia enters mammalian cells,” he said, “but I didn’t think it would be so easy and I wasn’t sure how you were going to do it.”
Well, he loved this. It was so simple, the postdoc makes a clone bank, throws it down on cells and gets what he wants. It reminded him of simpler times, like the 1960s when things were easier. This then led to a discussion of his favorite assay of all time, the “arm in the Potomac” assay, when science was really fun (and rather unregulated, I might add), told while he was sitting over the upright light microscope looking at E. coli within cells. When he was a young faculty member at Georgetown, he was convinced that hospitals were dumping antibiotics into the Potomac, and he had the perfect assay. One of his students had contact sensitivity to penicillin derivatives, so he had an idea. He would put her arm into the Potomac at various places and determine if antibiotics were being dumped based on her arm turning red. It didn’t take long before they found selected sites along the Potomac where they got a positive readout. Sure enough, these sites were close to hospitals, where effluent drained into the river, a beautiful demonstration of antibiotic misuse with the potential for selecting resistant organisms.
Well, you couldn’t really publish this kind of red-arm-in-the-river assay, so he had to figure out what to do with the data. At the time, Elliot Richardson was the Secretary of Health and Human Services, a man of great honor whose refusal of President Nixon’s request to fire special prosecutor Archibald Cox initiated the Saturday Night Massacre. Stanley respected Secretary Richardson greatly, so he wrote to the Secretary a sober account of his findings, describing the simple assay system. Richardson wrote back an equally sober reply, but I confess, I don’t remember what resulted from this letter exchange. I am sure that Stanley is convinced that he had an effect on cleaning up hospital practice, and I think he probably did, novel assay and all.
This was Stanley in a nutshell. He loved to keep things simple, loved a simple assay and loved to tell a great story.
Learn more about Stanley Falkow:
Learn more from Stanley Falkow:
Ralph Isberg performed his PhD dissertation in the laboratory of Michael Syvanen at Harvard Medical School prior to entering the Falkow laboratory at Stanford. After finishing his postdoctoral work, he became a faculty member at Tufts Medical School, where he has been since 1986. The simple cloning experiment described here led to his lifelong interest in determining how bacteria enter cells, and how some establish replication niches within these cells.
Feature Image Credit: Dr. Manuel Amieva